Tertiaryaminocyclobutanes with electronegative substituents



United States Patent 3,481,936 TERTIARYAMINOCYCLOBUTANES WITHELECTRONEGATIVE SUBSTITUENTS Kent C. Brannock, Kingsport, Tenn.,assignor to Eastman Kodak Company, Rochester, N.Y., a corporation of NewJersey No Drawing. Application Mar. 15, 1965, Ser. No. 440,017, nowPatent No. 3,369,024, dated Feb. 13, 1968, which is acontinuation-in-part of application Ser. No. 115,305, June 7, 1961.Divided and this application June 26, 1967, Ser. No. 648,973

Int. Cl. (307d 51/70, 29/10; C07c 87/34 U.S. Cl. 260-293 8 ClaimsABSTRACT OF THE DISCLOSURE Tertiaryaminocyclobutanes withelectronegative substituents useful as stabilizers, synergists,pharmaceuticals and chemical intermediates having the formula:

wherein X is a tertiaryamino group having a formula selected from thegroup consisting of:

Y is nitrile; Z is selected from the group consisting of hydrogen,mononuclear carbocyclic aryl, and nitrile; wherein at least one of thesubstituents R and R is hydrogen; and wherein each of R and R when takensingly, is selected from the group consisting of:

(a) hydrogen and (b) alkyl of 1 to 18 carbons;

wherein R when taken singly, is alkyl of 1 to 18 carbons when one of thesubstituents R and R is hydrogen and is selected from the groupconsisting of:

(a) alkyl of 1 to 18 carbons, (b) mononuclear carbocyclic aryl, and (c)tertiaryaminomethyl of the formula -CH X when both R and R are hydrogen;

wherein R and R when taken collectively with the carbon atoms to whichthey are attached, represent a saturated alicyclic group having to 8ring atoms;

wherein R and R when taken collectively with the carbon atom to whichthey are attached, represent a saturated carbocyclic group having 4 to 8ring carbon atoms;

wherein each of R and R when taken singly, is alkyl of 1 to 18 carbonsand R and R when taken collectively with the nitrogen atom to which theyare attached, represent a saturated heterocyclic group having 5 to 6ring atoms; and

each of the substituents R is the same alkylene group of 1 to 3 carbonatoms.

This application is a division of my copending application Ser. No.440,0l7, filed Mar. 15, 1965, now U.S. Patent No. 3,369,024, which wascopending with anda continuation-in-part of my applications Ser. No.115,305, filed June 7, 1961, now abandoned, and Ser. No. 34,881,

3,481,936 Patented Dec. 2, 1969 filed June 9, 1960, now abandoned, saidapplication Ser. No. 34,881 having been copending with and acontinuation-in-part of my application Ser. No. 837,579, filed Sept. 2,1959, now abandoned.

This invention relates to novel chemical compounds and to theirpreparation and more particularly to novel tertiaryaminocyclobutaneshaving electronegative substituents which can be represented by thegeneric formula:

and their preparation by the reaction of an enamine of the formula:

R R X([3=('3R3 and a substituted olefin of the formula:

(III) In the above generic formula for the noveltertiaryaminocyclobutanes of my invention, the substituents R and R whentaken singly, can be hydrogen or alkyl. At least one of the substituentsR and R must be hydrogen.

The substituent R when taken singly, is alkyl when only one of thesubstituents R and R is hydrogen and, when taken singly, is alkyl, arylor tertiaryaminomethyl when both R and R are hydrogen.

R and R when taken collectively with the carbon atoms to which they areattached, represent an alicyclic group of about 5 to about 8 ring atoms.

R and R when taken collectively with the carbon atoms to which they areattached, represent an alicyclic group of about 4 to about 8 carbonatoms.

The substituent X is a tertiaryamino group, and the substituent Y, whentaken singly, is an electronegative radical selected from the groupconsisting of nitrile, nitro, alkylsulfonyl, alkoxycarbonyl and carboxy.The substituent Z, when taken singly, can be hydrogen, aryl, or one ofthe electronegative substituents which Y can be, i.e., nitrile, nitro,alkylsulfonyl, alkoxycarbonyl or carboxy.

The substituents Y and Z, when taken collectively with the carbon atomsto which they are attached, can represent anN-alkyl-Z,5-dioxopyrrolidin-3,4-y1ene group.

In the formulae for the enamine reactants and the substituted olefinreactants useful in manufacturing the novel tertiaryaminocyclobutanes ofmy invention, the substituents X, R R and R have the meanings previouslydiscussed for the tertiaryaminocyclobutanes.

The substituent Y of the substituted olefin, when taken singly, is anelectronegative radical such as nitrile, nitro, alkylsulfonyl oralkoxycarbonyl and the substituent Z of the substituted olefin, whentaken singly, can be hydrogen, aryl, nitrile, nitro, alkylsulfonyl oralkoxycarbonyl. The substituents Y and Z of the substituted olefin, whentaken collectively with the carbon atoms to which they are attached,represent an N-a1kyl-2,4-dioxop yrrolidin-3,4y1ene group.

The novel tertiaryaminocyclobutanes having electronegative substituentsare useful as sludge and color stabilizers for hydrocarbon fuel oils, assynergists for gasoline antioxidants, and as pharmaceuticals, e.g.,analgesics, and as pharmaceutical and chemical intermediates.

The tertiaryaminocyclobutanes of my invention generally fall into threeclasses, depending upon the type of enamine reactant used in theirpreparation.

Enamines having no ,8 hydrogen atom, i.e., enamines derived from thereaction of secondary amines and aldehydes having one a hydrogen atom,when reacted with a substituted olefin in accordance with the process ofthe invention, yield tertiaryaminocyclobutanes in which the substituentR is hydrogen, i.e., tertiarylaminocyclobutanes of the formula:

in which the substituents R R X, Y and Z are as hereinbefore defined. Inaccordance with the previous defini tions, each of R and R in theFormula IV, above, when taken singly, is alkyl and R and R when takencollectively with the carbon atom to which they are attached, representan alicyclic group having about 4 to about 8 ring atoms.

Enamines having an a and a 5 hydrogen atom, i.e., enamines derived fromthe reaction of secondary amines and aldehydes having two a hydrogenatoms, when reacted with a substituted olefin in accordance with theprocess of the invention, yield tertiaryaminocyclobutanes in which thesubstituents R and R are hydrogen, i.e., tertiaryaminocyclobutanes ofthe formula:

YCHCI-I-Z in which the substituents R X, Y and Z are as hereinbeforedefined. In accordance with the previous definitions, R is alkyl, arylor tertiaryaminomethyl.

Enamines having no a hydrogen atoms, i.e., enamines derived from thereaction of secondary amines and ketones having two a hydrogen atoms,when reacted with a substituted olefin in accordance with the process ofthe invention, yield tertiaryaminocyclobutanes in which the substituentR is hydrogen, i.e., tertiaryaminocyclobutanes of the formula: (VI) 1'1XC(|3HR3 Y-oH-oHz in which the substituents R R X, Y and Z are ashereinbefore defined. In accordance with the previous definitions, eachof R and R when taken singly, is alkyl and R and R when takencollectively, represent an alicyclic group having about 4 to about 8ring atoms.

The enamines used in the process of my invention are prepared by thereaction of certain aldehydes or ketones with a secondary amine asdescribed in US. Patent 2,578,787. The general reaction between thealdehyde or ketone and the secondary amine can be represented by theequation:

R2 If} R2 X-H IU-C-C'lH-R Xo=b-R H2O In the above equation, thesubstituents R R R and X have the meanings previously assigned.

The preparation of enamines having no 5 hydrogen atom from secondaryamines and aldehydes having one a hydrogen atom, i.e., the enamines usedin the process of the invention to prepare the tertiaryaminocyclobutanesof the Formula IV, can be represented by the equation:

The preparation of enamines having an a and a #3 hydrogen atom fromsecondary amines and aldehydes having two a hydrogen atoms, i.e., theenamines used in the preparation of the tertiaryaminocyclobutanes ofFormula V can be represented by the equation:

The preparation of enamines having no at hydrogen atom from secondaryamines and ketones having two on hydrogen atoms, i.e., the enaminesemployed in preparing the tertiaryaminocyclobutanes of Formula VI can berepresented by the equation:

The substituents R R and R of the preceding formulae, when alkyl, aretypically alkyl of 1 to about 18 carbon atoms and are preferably loweralkyl, e.g., alkyl of l to about 5 carbon atoms. Examples of the alkylsubstituents which R R and R can be include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-amyl, n-hexyl, n-heptyl,2-ethylhexyl, n-decyl, n-dodecyl, tridecyl, pentadecyl, octadecyl, etc.

The substituent R when aryl, is typically aryl of 6 to about 10 carbonatoms and is preferably mononuclear carbocyclic aryl of 6 to about 10carbon atoms. Examples of the aryl substituents which R can be includephenyl, naphthyl, o-tolyl, m-tolyl, p-tolyl, xylyl, etc.

The substituent R when tertiaryaminomethyl, can be represented by theformula XCH wherein X is a tertiaryamino group as described hereinbeforeand as more fully described hereinafter.

The substituents R and R when taken collectively with the carbon atomsto which they are attached to represent an' alicyclic group having 5 to8 ring atoms, typically represent a carbocyclic or heterocyclic group.Examples of the carbocyclic or heterocyclic groups represented by R andR when taken collectively with the carbon atoms to which they areattached, are groups such as 1,2-cyclopentylenc; 1,2-cyclohexylene;1,2-cycloheptylene; 1,2-cyclooctylene; tetrahydrofuran-3,4-ylene;tetrahydrofuran-2,3-ylene; N-methylpiperidin 2,3 ylene; N-methylpiperidin-3,4-ylene; etc. Preferred are the saturated alicyclicgroups. Examples of compounds in which R and R are taken collectivelywith the carbon atoms to which they are attached to represent asaturated alicyclic group are bicyclic compounds having the formulae:

The substituents R and R when taken collectively with the carbon atom towhich they are attached to represent an alicyclic group having 4 to 8ring carbon atoms, preferably represent a saturated carbocyclic groupsuch as cyclobutylidene, cyclopentylidene, cyclohexylidene,cycloheptylidene, cyclooctylidene, etc. Examples of typical compounds inwhich R and R when taken collectively with the carbon to which they areattached, represent such an alicyclic group are those of the formulae:

CHz-CH2 CHzCHg-CH2 OH: and X-CHCCHz-CH1 Y-CH-CH-Z in which X, Y and Zare as hereinbefore defined.

The substituent X is a tertiaryamino group, i.e., an amino group havingno labile hydrogen atoms. Typical of the suitable tertiaryamine groupsof the tertiaryaminocyclobutane are those which can be represented bythe formulae:

in which Y, Z, R R and R are as hereinbefore defined; R and R wh n takensingly, are alkyl and, when taken collectively with the nitrogen atom towhich they are attached, represent a heterocyclic group having about 5to about 6 ring atoms; and each of the substituents R is the samealkylene group of 1 to 3 carbon atoms. Typical of the suitabletertiaryamine groups of the enamine reactant are those of the formulae:

in which R R R R R and R are as hereinbefore defined and more fullydescribed hereinafter.

The substituents R and R when alkyl, are typically alkyl of l to about18 carbon atoms and are preferably lower alkyl, e.g., alkyl of 1 toabout 5 carbon atoms. Examples of the alkyl substituents which R and Rcan be include methyl, ethyl, n-propyl, n-butyl, isobutyl, tertbutyl,n-amyl, n-hexyl, n-heptyl, Z-ethylhexyl, n-decyl, ndodecyl, tridecyl,pentadecyl, octadecyl, etc.

The substituents R and R when taken collectively with the nitrogen atomto which they are attached to represent a heterocyclic ring of about 5to about 6 ring atoms, preferably represent a saturated heterocyclicring such as pyrrolidinyl, piperidino, morpholino, etc.

The alkylene groups represented 'by R are preferably ethylene groups.The tertiaryaminocyclobutane then has the formula:

Z( )H( 3HY CHzCfiz Y( }H( JH-Z and the enamine from which the abovetertiaryaminocyclobutane is prepared has the formula:

wherein Y, Z, R R and R have the meanings assigned hereinbefore.

The substituents Y and Z, when electronegative radicals, are electronWithdrawing groups. When the substituents Y and Z are alkylsulfonyl oralkoxycarbonyl, they can be represented by the formulae SO R and COOR inwhich R is alkyl. The alkyl group R is typically alkyl of 1 to 18 carbonatoms and is preferably lower alkyl, e.g., alkyl of 1 to about 5 carbonatoms. Examples of the alkyl substituents represented by R are groupssuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-amyl, n-hexyl, n-heptyl, 2-ethylhexyl, n-decyl, n-dodecyl,tridecyl, pentadecyl, octadecyl, etc.

The substituent Z, when aryl, is typically aryl of 6 to about 10 carbonatoms and is preferably mononuclear carbocyclic aryl of 6 to about 10carbon atoms. Examples of the aryl substituents which Z can be includephenyl, naphthyl, o-tolyl, m-tolyl, p-tolyl, xylyl, etc.

The compounds in which Y and Z, when taken collectively with the carbonatoms to which they are attached, represent anN-alkyl-2,4-dioxopyrrolidin-3,4-ylene gr up having the formula:

in which X, R R R and R have the meanings previously assigned.

Also included within the scope of the invention are acid addition saltsof the hereinbefore described tertiaryaminocyclobutanes. These salts arealso useful as pharmaceuticals and as pharmaceutical or chemicalintermediates and are prepared by the conventional technique ofneutralizing the tertiaryaminocyclobutane with an organic or inorganicacid. Typical of the useful salt forming acids are those such ashydrochloric acid, sulfuric acid, phosphoric acid, citric acid, aceticacid, maleic acid, molonic acid, tartaric acid, etc.

As previously stated, the novel tertiaryaminocyclobutanes havingelectronegative substituents are prepared by reacting certain enamineswith certain substituted olefins. The process of the invention can berepresented by the following general equation:

Xd=c :R YOH=GH-Z X-oo-R Y-(IH-C'lH-Z in which R R R X, Y and Z have themeanings hereinbefore assigned.

In general, the process of the invention is carried out by contactingthe enamine and the olefin at a tempera ture below the temperature ofthermal decomposition of the reactants or products.

Suitable reaction temperatures depend upon the characteristics of thereactants and products. In the case of the preparation oftertiaryaminocyclobutanes from substituted olefins and enamines havingno 5 hydrogen atom, i.e., the enamines of Formula B reactiontemperatures of about 0 C. up to about 200 C. or higher are generallysuitable so long as the temperature of thermal decomposition of thereactants and products is not exceeded. A preferred temperature rangefor eifecting the reaction between a substituted olefin and an enaminehaving no 5 hydrogen atoms is from about 50 C. to about 190 C.

In the case of the preparation of tertiaryaminocyclobutanes fromsubstituted olefins and enamines having an on and a [3 hydrogen atom,i.e., the enamines of Formula C, reaction temperatures of from about 0C. up to about C. or higher are generally suitable so long as thetemperature of thermal decomposition of the reactants and products isnot exceeded.

In the case of the preparation of tertiaryaminocyclobutanes fromsubstituted olefins and enamines having no or hydrogen atom, i.e., theenamines of Formula D, reaction temperatures of from about 0 C. up toabout 55 C. or higher are generally suitable so long as the temperatureof thermal decomposition of the reactants and products is not exceeded.

The relative proportions of the reactants can be varied Widely incarrying out the process of the invention. Thus, a stoichiometricequivalent of the enamine and the substituted olefin can be employed ora stoichiometric excess of either the enamine or the substituted olefincan be used. In general, it is preferred to employ stoichiometricequivalents of the reactants in accordance with usual chemical practice.

The process of the invention is ordinarily carried out at atmosphericpressure. However, susbatmospheric or superatmospheric pressures can beemployed and are sometimes preferred. No catalyst is required to effectthe reaction.

The process of the invention can be carried out with a solvent orwithout a solvent. Examples of suitable solvents include acetonitrile,propionitrile, butyronitrile, dimethyl formamide, dimethyl acetamide,propylene carbonate, ethylene carbonate, methyl isoamyl ketone,methanol, ethanol, nitrobenzene, dimethylsulfoxidle, ethyl acetate,benzene, heptane, carbon tetrachloride, dioxane diethyl ether, dibutylether, etc. Preferred are the solvents having a high dielectric constantand particularly preferred, when a solvent is employed, is a dipolaraproti'c solvent.

Typical reaction times vary from a few minutes to one or more days,e.g., 24 to 48 hours or longer, depending mainly on the reactiontemperature and reactants employed. However, longer or shorter reactionperiods can be utilized.

The process of the invention affords the tertiaryaminocyclobutanes inhigh yields. The tertiaryaminocyclobutane product can be worked-up orpurified by conventional purification methods, the preferred methodvarying with the properties of the product. Particularly effectivepurification methods include fractional distillation under reducedpressure and fractional crystallization from solvents. However, otherpurification methods, e.g., solvent extraction, chromatographicadsorption, molecular distillation, etc., can be employed and are oftenpreferred. In some instances, it is unnecessary to purify thetertiaryaminocyclobutane since the crude reaction product issatisfactory for the intended use, e.g., when thetertiaryaminocyclobutane is employed as a chemical or pharmaceuticalintermediate.

The compounds of the invention in which the substituents Y or Z arecarboxyl are most readily prepared from the corresponding esters, e.g.,by hydrolysis of the corresponding ester. The hydrolysis of the estercan be accom plished by conventional procedures, e.g., by heating withan aqueous dilute mineral acid.

The following examples illustrate the process and compounds of theinvention.

EXAMPLE 1 A mixture of N-isobutenylpiperidine (69.5 g., 0.5 mole) andacrylonitrile (26.5 g., 0.5 mole) was heated in an autoclave for 2 hoursat 175 C. Distillation of the reaction mixture gave 3.5 g. ofacrylonitrile, 17 g. of N- isobutenylpiperidine, and 59.5 g. (62%conversion) of 3,3 dimethyl-Z-(piperidino)cyclobutanecarbonitrile, B.P.9499 C. at 1.82.0 mm., N 1.4780.

EXAMPLE 2 A mixture of N-isobutenylpiperidine (139 g., 1.0 mole) andmethyl acrylate (86 g., 1.0 mole) was heated in an autoclave for twohours at 180 C. Distillation of the reaction mixture gave, after removalof the unreacted methyl acrylate and N-isobutenylpiperidine, 157 g. (70%conversion) of methyl 3,3-dimethyl-2-(piperidino)cyclobutanecarboxylate,B.P. 103 C. at 3.7 mm., N 1.4705.

EXAMPLE 3 To B-nitrostyrene (47.5 g., 0.32 mole) was added N,N-dimethylisobutenylamine (33 g., 0.33 mole). The mixture was stirredmanually and the temperature rose to 92 C. over a two-minute period andthen began to drop slowly. After about 15 minutes, the reaction mixturecrystallized. It was triturated with hexane and filtered to give 74.5 g.(94% yield) of crude N,N-dimethyl-2,2-dimethyl-3-phenyl-4-nitrocyclobutylamine, M.P. 8691 C. Onrecrystallization from hexane, the product melted at 90-92 C. Analysisshowed 67.91% carbon, 8.34% hydrogen and 11.49% nitrogen as compared tocalculated values of 67.72% carbon, 8.11% hydrogen and 11.28% nitrogen.

EXAMPLE 4 Reacted as described in Example 3, a 0.32 mole portion offi-nitrostyrene and a 0.33 mole portion of N- isobutenylpiperidine gavea substantially quantitative yield of1-(2,2-dimethyl-4-nitro-3-phenylcyc1obutyl)piperidine, M.P. 7072 C.Analysis showed 70.57% carbon, 8.52% hydrogen, and 9.67% nitrogen ascompared to calculated values of 70.80% carbon, 8.39% hydrogen and 9.71%nitrogen.

EXAMPLE 5 A mixture of N,N-dimethylisobutenylamine (297 g., 3 moles) andmethyl acrylate (258 g., 3 moles) was heated for 2 hours at 170 C. in anautoclave. Distillation of the reaction mixture gave, after removal ofunreacted starting materials, 419 grams (75% yield) of methyl 3,3-dimethyl 2 dimethylaminocyclobutanecarboxylate, B.P. 49-50 C. at 1.5 mm,N 1.4448.

8 EXAMPLE 6 A mixture of N,N-dimethylisobutenylamine (297 g., 3 moles)and acrylonitrile (159 g., 3 moles) was heated for 2 hours at 170 C. inan autoclave. Distillation of the reaction mixture gave, after removalof unreacted starting materials, 292 grams (64% yield) of3,3-dimethyl-2-dimethylaminocyclobutanecarbonitrile, B.P. 4445 C. at ca.1 mm., N 1.4531.

EXAMPLE 7 A mixture of N,N-dimethylisobutenylamine (82 g., 0.83 mole)and diethylmaleate (172 g., 1 mole) was heated under reflux for 18hours, during which time the temperature of the mixture rose from C. to162 C. Distillation of the reaction mixture gave, after removal ofunreacted starting materials, 150.5 g. (67% yield) of diethyl 3,3dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate, B.P. 93-94 C. at1.5 mm., N 1.4502.

EXAMPLE 9 A mixture of N-isobutenylpiperidine (208.5 g., 1.5 moles) anddiethylmaleate (322.5 g., 1.877 moles) was heated at C. for 5 /2 hours.Distillation of the reaction mixture gave, after removal of unreactedstarting materials, 274 g. of diethyl3,3-dimethyl-4-(piperidino)cyclobutane-1,2-dicarboxylate, B.P. 113120 C.at 1.0-1.5 mm., N 1.4663.

EXAMPLE 10 A one mole proportion of N-(Z-ethyl-1-butenyl)piperidine wasreacted with a one mole proportion of methyl acrylate for 2 hours at C.in an autoclave. The resulting reaction product was distilled toseparate the cyclobutane derivative, methyl 3,3-diethyl-2-(piperidino)cyclobutanecarboxylate, B.P. 1l9121 C. at 2 mm., N 1.4788.

EXAMPLE 11 A one mole proportion of 1,4-diisobutenylpiperazine and a twomole proportion of methyl acrylate were reacted for 2 hours at 170 C. inan autoclave. The resulting reaction product was triturated with hexaneand filtered to give the cyclobutane derivative, 1,4-bis(4-methoxycarbonyl 2,2 dimethylcyclobutyl)piperazine, M.P. 148 C.

EXAMPLE 12 A one mole proportion of N-isobutenylmorpholine was reactedwith a one mole proportion of methyl acrylate for 2 hours at 170 C. inan autoclave. The resulting reaction product was distilled to separatethe cyclobutane derivative, methyl 3,3 dimethyl2-morpholinocyclobutanecarboxylate, B.P. 101102 C. at 2.2 mm., N 1.4711.

EXAMPLE 13 A one mole proportion of l-cyclohexylidenemethylpiperidinewas reacted with a one mole proportion of methyl acrylate for 2 hours at170 C. in an autoclave. The resulting reaction product was distilled toseparate the cyclobutane derivative, methyl l-piperidino-spiro-[3.5]nonane-2-carboxylate, B.P. 11542.0 C. at 0.5-1 mm, N 1.4963.

9 EXAMPLE 14 A one mole proportion of N,N-di-n-butylisobutenylamine wasreacted with a one mole proportion of methyl acrylate for 2 hours at 170C. in an autoclave. The resulting reaction product was distilled toseparate the cyclobutane derivative, methyl3,3-dimethyl-2-di-n-butylaminocyclohutanecarboxylate, B.P. 98 C. at ca.1.5 mm., N 1.4543.

EXAMPLE 15 A one mole proportion of N,N-diisobutylisobutenylamine wasreacted with a one mole proportion of methyl acrylate for 2 hours at 170C. in an autoclave to give the resulting reaction product, methyl3,3-dimethyl-2-diisobutylaminocyclobutanecarboxylate, B.P. 93-100" C. atca. 2 mm., N 1.4510.

EXAMPLE 16 N-l-butenylpiperidine (69.5 g., 0.5 mole), 150 ml. ofacetonitrile and methyl acrylate (43 g., 0.5 mole) were combined. Therewas a mildly exothermic reaction with the temperautre rising to 30 C.for about 1 hour and then dropping to room temperature. After standingat room temperature for 2 days, distillation gave, after removal of thesolvent and low boilers, 86 g. (77%) of methyl3-ethyl-2-piperidinocyclobutanecarboxylate, B.P. 87-90 C. at 0.75 mm., N1.4733.

EXAMPLE 17 When a mixture of N-l-butenylpiperidine (45 g., 0.32 mole),75 ml. of acetonitrile and diethyl maleate (55 g., 0.32 mole) wasallowed to stand 24 hours and subjected to molecular distillation at69-70 C. at 100' microns, a 45% yield of diethyl4-ethy1-3-piperidino-1,2cyc1obutanedicarboxylate, N 1.4690, wasobtained.

EXAMPLE 18 When Example 16 was repeated and the reaction mixture wasrefluxed for 3 hours at 86 C. (rather than standing for 2 days), an 82%yield of the same product was obtained.

EXAMPLE 19 N-l-propenylpiperidine (62 g., 0.5 mole), methyl acrylate (43g., 0.5 mole) and 100 ml. of acetonitrile were refluxed at 85 C. for 2hours and the mixture was distilled to give 71 g. (67.5% yield) ofmethyl 3-methyl-2- piperidinocyclobutanecarboxylate, B.P. 70-75 C. at0.5 mm., N 1.4741.

EXAMPLE 2 Example 16 was repeated without acetonitrile as a solvent. Thesame product was obtained, but only in 54% yield. By following thereaction by means of the infrared spectrum of the reaction mixture, itis found that the rate is appreciably faster in solvents of highdielectric constant such as acetonitrile.

EXAMPLE 21 Reaction of N,N-dirnethyl-l-butenylamine (43 g., 0.43 mole)and methyl acrylate (37 g., 0.43 mole) in 100 ml. of acetonitrile for 20hours at room temperature gave 69 g. (87%) of methyl3-ethyl-2-dimethylaminocyclobutanecarboxylate, B.P. 52-53" C. at 1 mm.,N 1.4454.

EXAMPLE 22 By the method described in Example 21,N,N-dimethyll-butenylamine and diethylmaleate gave a 79% yield ofdiethyl 4 ethyl-3-dimethylamino-1,2-cyclobutanedicarboxylate, B.P. 95-98C. at 0.8 mm., N 1.4482.

EXAMPLE 23 N-1-propenylpiperidine (36 g., 0.288 mole), 75 ml. ofacetonitrile and methyl vinyl sulfone (30 g., 0.283 mole) were refluxedfor 3 hours at 85 C. Distillation 10 gave 37 g. (57%) of3-methyl-2-piperidino-1-methylsulfonylcyclobutane, B.P. 172--130 C. at 4mm., N 1.4954.

EXAMPLE 24 Methyl 3 phenyl 2 dimethylaminocyclohutanecarboxylate, B.P.49 C. at 1 micron, N 1.5190, was prepared by reacting methyl acrylateand an enamine having the formula:

in substantially equal molar proportions as described in Example 16.

EXAMPLE 25 Diethyl 4 phenyl 3-dimethylamino-1,2-cyclobutanedicarboxylate, B.P. 79 C. at 1 micron, N 1.5015, was prepared byreacting diethylmaleate and the enamine described in Example 24 insubstantially equal molar proportions as described in Example 16.

EXAMPLE 26 Methyl 3-dimethylaminomethyl 2dimethylaminocyclobutanecarboxylate, B.P. 78-82 C. at .75 mm., N 1.4592,was prepared by reacting methyl acrylate and 1,3-bisclimethylamino-l-propene in substantially equal molar proportions asdescribed in Example 16.

EXAMPLE 27 Diethyl 4 dimethylaminomethyl 3 dimethylamino-1,2-cyclobutanedicarboxylate, B.P. 50 C. at 6 microns, N 1.4562, wasprepared by reacting diethylmaleate and 1,3-bis dimethylamino-Lpropenein substantially equal molar proportions as described in Example 16.

EXAMPLE 28 N-(l-cyclopentenyl)piperidine, methyl acrylate, andacetonitrile containings a pinch of hydroquinone were combined. Anexothermic reaction occurred, but the temperature of the reactionmixture was maintained below 30 C. by intermittent cooling. Afterstanding for 4 hours at room temperature, the solvent was removed bydistillation under reduced pressure while maintaining the temperaturebelow 30 C. Infrared anaylsis of the undistilled material disclosed thepresence of methyl l-piperidino-bicyclo[3.2.01heptane-l-carhoxylate.

EXAMPLE 29 N-(1-cyclopentenyl)piperidine (75.5 g., 0.5 mole),diethylmaleate (86 g., 0.5 mole), and acetonitrile ml.), were combined.An exothermic reaction occurred and the temperature rose to a maximum of63 C. within 17 minutes. After letting the mixture stand for 1 hour, thesolvent was removed by distillation under reduced pressure, leaving g.of crude diethyl l-piperidinobicyclo- [3.20]heptane-S,7-dicarboxylate.An infrared spectrum on this material was consistent with the assignedstructure.

EXAMPLE 30 N-(l-cyclohexenyl)dimethylamine (75 g., 0.6 mole),diethylmaleate (103 g., 0.6 mole), and acetonitrile (100 ml.) werecombined. An exothermic reaction occurred and the temperature wasmaintained below 40 C. by means of intermittent cooling. After standingfor 3 /2 hours, the mixture was divided into two equal portions. Oneportion was distilled in an alembic type pot molecular. still to give 81g. (91%) of diethyll-dimethylaminobicycl0[4.2.0]octane-7,8-dicarboxylate, boiling at 65-67"C. at ca. 15n. The infrared spectrum was in agreement with the assignedstructure.

Analysis.-Calcd. for C H O C, 64.7; H, 9.17; N, 4.72. Found: C, 64.52;H, 9.02; N, 4.54.

1 1 EXAMPLE 31 N-(l-cycloheptenyl)pyrrolidene (30 g., 0.18 mole),diethyl maleate (31.2 g., 0.18 mole) and acetonitrile (75 ml.) werecombined and let stand at room temperature for one day. The solvent Wasremoved by distillation under reduced pressure, leaving 61 g. (theory=61g.) of diethyl 1 pyrrolidinebicyclo[5.2.0]nonane-8,9-dicarboxylate, N1.4932. The infrared spectrum supported the assigned structure.

EXAMPLE 32 In a manner similar to Example 31, N-(l-cyclooctenyl)piperidine (13 g., 0.067 mole) and diethyl maleate (11.6 g., 0.067 mole)were allowed to react to give 24 g. (theory:24.8 g.) of diethyll-piperidinebicyclo[6.2.0] decane-9,IO-dicarboxylate, N 1.4918.

EXAMPLE 33 N methyl 4 (1 pyrrolidinyl) 1,2,3,6 tetrahydropyridine (16.6g., 0.1 mole) and diethyl maleate (17.2 g., 0.1 mole) were combined. Thetemperature of the mixture rose to a maximum of 665 C. after fiveminutes and then dropped back to room temperature. After 3 hours, aninfrared spectrum of the product showed no double bond absorption. Theyield of diethyl 3-methyl-6- pyrrolidinyl-3-azabicyclo [4.2.0]octane-7,8 dicarboxylate, a viscous liquid with N 1.4893, is virtuallyquantitative.

EXAMPLE 34 N (1 ethyl 1 propenyl)dimethylamine (33 g., 0.29 mole),methyl acrylate g., 0.29 mole), and acetonitrile (50 ml.) containing apinch of hydroquinone were combined. A mild exothermic reaction tookplace and the temperature was maintained below C. by intermittentcooling. After 3 hours standing an infrared spectrum obtained on themixture showed only a very weak absorption bond in the double bondregion (6-6.1 ,lL). An NMR spectrum on this material was consistent withthe structure methyl 3 methyl 2 dimethylaminocyclobutane-l-carboxylate.

EXAMPLE 35 N (1 ethyl 1 propenyl)dimethylamine (20 g., 0.177 mole),diethyl maleate (30.5 g., 0.177 mole), and acetonitrile (50 ml.)containing a pinch of hydroquinone were combined. The temperature of themixture rose to 54 C. within 18 minutes. The mixture was allowed tostand at room temperature for three days, after which it was strippedunder reduced pressure to 75 C. at 0.5 mm. There was left 23 g. (46%) ofdiethyl-4-methyl-3-ethyl- 3-dimethylaminocyclobutane 1,2 dicarboxylate,N 1.4602. Infrared and NMR spectra were consistent with the proposedstructure.

EXAMPLE 36 1 (2,5 dihydrofuran 3 yl)pyr-rolidine, B.P. 55- 59 C. at 0.3mm., N 1.5148, was prepared from 3- ketotetrahydrofuran and pyrrolidine.The structure of this enamine was shown by its NMR spectrum which ruledout the isomeric 4,5-dihydrofuran structure. To the above enamine (16.8g., 0.12 mole) diethyl maleate (20.7 g., 0.12 mole) was addedportionwise with cooling to keep the temperature below 50 C. After thereaction was complete, an infrared spectrum showed the completedisappearance of the enamine and maleate double bond absorptions. Theproduct, a viscous oil, N 1.4845, is essentially pure diethyll-(l-pyrrolidino) 3 oxabicyclo [3.2.0]heptane-6,7-dicarboxylate and isobtained in quantitative yield.

EXAMPLE 37 To N (1 cyclohexenyl)morpholine (47 g., 0.28 mole) was addedN-ethylmaleimide (35 g., 0.28 mole). An exothermic reaction took place,and intermittent cooling was used to keep the temperature below C. Afterthe reaction was complete, an infrared spectrum of the mixture showed nodouble bond absorption. The product, l-rnorpholinobicyclo[4.2.0]octane7,8 dicarboxylic acid, N- ethylimide, is a viscous oil with N 1.5208.

The following examples illustrate novel tertiaryaminocyclobutane saltswithin the scope of the invention and the use of the compounds of theinvention as chemical intermediates in the preparation of primary aminesand primary alcohols which are useful for a variety of purposes, e.g.,the alcohols can be esterified with a dicarboxylic acid to form diesterswhich are useful plasticizers for synthetic resins.

EXAMPLE 38 To a reaction vessel was added a 7.7 part by weight portionof isopropyl alcohol and a 1.09 part by weight portion of citric acid.The resulting mixture was heated with stirring to 50 C. and maintainedat 50 C. until solution was achieved. Then a 1.54 part by weight portionof diethyl 3,3-dimethyl 4 dimethylaminocyclobutane- 1,2-dicarboxylatewas added to the solution. The resulting mixture was heated to 6065 C.and held at that temperature for 30 minutes. The reaction mixture wasthen cooled to about 30 C. over a period of 2 hours. The resultingmixture was then cooled to 1520 C. and stirred for 1214 hours to efiecta crystallization of the citrate salt of diethyl 3,3 dimethyl 4dimethylaminocyclobutane-1,2-carboxylate. The resulting mixture wasfiltered and the prepared salt recovered. ln a similar manner, thecorresponding hydrochloride salt can be prepared by substitutinghydrochloric acid for the citric acid.

EXAMPLE 39 A 31 g. portion of diethyl 3,3-dimethyl 4 (l-piperidino)cyclobutane 1,2 dicarboxylate was combined with 100 ml. of concentratedhydrochloric acid and heated under reflux for 6 hours. The solution wasevaporated on a steam bath and the remaining solid residue trituratedwith hot n-butanol to give 17 g. of the hydrochloride salt of3,3-dimethyl 4 (l-piperidino)cyclobutane-12 dicarboxylic acid, M.P.234-5 C.

EXAMPLE 40 By the method described in Example 39, the hydrochloride saltof 3,3'dimethyl-4-dimethylaminocyclobutane- 1,2 dicarboxylic acid, M.P.about 200 C., was prepared from diethyl3,3-dimethyl-4-dimethylaminocyclobutane 1,2 dicarboxylate andhydrochloric acid.

EXAMPLE 41 A 150 g. portion of 3,3 dimethyl 2 (1 piperidino) cyclobutanecarbonitrile in 200 ml. of methanol was hydrogenated over 10 g. of Raneynickel in the presence of g. of anhydrous ammonia at C. under 1000p.s.i. of pressure. The resulting reaction mixture was filtered anddistilled to give 78 g. of 3,3-dimethyl-2-(l-piperidino)cyclobutanemethylamine, B.P. 6365 C. at 1 mm., N 1.4841.

EXAMPLE 42 A 137 g. portion of 3,3-dimethyl 2 dimethylaminocyclobutanecarbonitrile in ml. of methanol was hydrogenated over 7 g. of Raneynickel in the presence of 75 g. of anhydrous ammonia at 100 C. and under1000 p.s.i. of pressure. The reaction mixture was filtered and distilledto give, after removal of methanol, a 9 g. forerun, B.P. 36-51 C. at 40mm.; 21 g. of 3,3-dimethylpiperidine, B.P. 5152 C. at 40 mm., N 1.4476;an intermediate fraction or cut of 4 g., B.P. 52101 C. at 40 mm, and64.5 g. of 3,3-dimethyl-2-dimethylaminocyclobutanemethylamine, B.P.101103 C. at 40 mm., N

EXAMPLE 43 A solution of 56 g. of methyl 3,3-dimethyl 2dimethylaminocyclobutanecarboxylate in 250 m1. of diethyl ether wasadded dropwise to a solution .of 7.6 g. of lithium aluminum hydride in150ml. of diethyl ether at a rate suffici'ent'to maintain the ether atreflux. The resulting mixture was stirred 'for'one hour andfthen 8.8-'g. of ethyl acetate wasadded followed by 18 ml. of water. The resultingmixture 'was filtered and the filtrate distilled to give,'after' removalof the ether solvent, 30 g. of 3,3-dimethyl 2 dimethylaminocyclobutanemethanol, B.P. 71-73 C. at 1 mm' N 1.4644.

EXAMPLE 44 By the method described in Example 43, 3,3-dimethyl-2-morpho1inocyclobutane methanol, B.P. 99-103 C. at 1.5-1.8 mm., MP.151-3 C. was prepared by substituting methyl3,3-dimethyl-2-morpholinocyclobutanecarboxylate for the methyl3,3-dimethy1-2-dimethylaminocyclobutanecarboxylate reactant.

EXAMPLE 45 By the method described in Example 43, l-piperidinospiro[3.5]nonane-2-methanol, M.P. 105-106.5 C., was prepared bysubstituting methyl-l-piperidinospiro[3.5] nonane-Z-carboxylate for themethyl 3,3-dirnethyl-2-dimethylaminocyclobutanecarboxylate reactant.

EXAMPLE 46 By the method described in Example 43, 3,3-dimethyl-4-dimethylaminocyclobutane-1,2-dimethanol, B.P. 133-6 C. at 1 mrn., N1.4821, was prepared by substituting diethyl3,3-dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate for the methyl3,3 dimethyl-2-dimethylaminocyclobutanecarboxylate reactant.

EXAMPLE 47 By the method described in Example 43, 3,3-'dimethyl-4-pyrrolidinocyclobutane-1,Z-dimethanol, 8.1. 151-154 C. at 1.5-1.8 mm.,N 1.4986, was prepared by substituting dimethyl3,3-dimethyl-4-pyrrolidinocyclobutane-l, Z-dicarboxylate for the methyl3,3-dimethyl-2-dimethylaminocyclobutanecarboxylate reactant.

EXAMPLE 48 N-(l-cyclopentyDdimethylamine (55 g., 0.5 mole), methylacrylate (43 g., 0.5 mole), and acetonitrile (150 ml.) containing apinch of hydroquinone, were reacted according to the procedure describedin Example 28, keeping the temperature of the mixture below 30' C. Afterremoval of the solvent, the residue comprising94 g. of methyl1-dimethylaminobicyclo[3.2.0]heptane-7-carboxylate was dissolved inanhydrous ether (100 ml.) and added dropwise to a slurry of lithiumaluminum hydride (13 g., 0.34 mole) in anhydrous ether (300 -ml.). Theether refluxed during this addition. The reaction mixture was allowed tostand overnight. Ethyl acetate ml.) and water (75 ml.) were added andthe solids were filtered off. Evaporation of the other from the filtrateon a steam bath left 101 g. of residue. This residue was mixed withwater (200 ml.) and concentrated hydrochloric acid (50 g.) and heated onthe steam bath for 3 hours, cooled, extracted twice with ether (50 ml.),and made the aqueous phase basic with 10% sodium hydroxide solution,whereupon an oil separated. The oil was separated by extraction withether and distilled to give 33 g. (39% based on 0.5 mole of methylacrylate) of crude 1-dimethylaminobicyclo[3.2.0]heptane-7-methanol, B.P.96-101 C. at ca. 1 mm., N 1.4912. The existence of an absorption band at5.78- 5.79p in the infrared spectrum of this material suggested thepresence of a carbonyl component as an impurity.

The above reaction was repeated, using 0.47 mole quantities of startingmaterial. There was obtained 30 g. (38%) ofl-dimethylamlnobicyclo[3.2.0]heptane-7-methanol, which likewisecontained a carbonyl impurity. The crudel-dimethylaminoblcyclo[3.2.0]-heptane-7-methanol from the above twopreparations (63 g., 0.37 mole) was dissolved in a solution of water(100 ml.) and concentrated hydrochloric acid' (35 ml.) and the resultingsolution extracted 7 times with ml. portions of ether. Evaporation ofthe combined. extracts on a steam bath left 23.5 g. of neutral material.The acidic aqueous phase was made basic with dilute sodium hydroxidesolution and the oil layer which separated removed by extraction withether. Distillation of this etheral extract gave 27 g. ofl-dimethylaminobicyclo[3.2.0]heptane-7- methanol, B.P. 96-99 C. at ca.0.5 mm., N 1. 4975. The infrared and NMR spectra were consistent withthe proposed structure.

AnaIysis.-Calcd. for C H NO: C, 70.9; H, 11.31. Found: C, 70.78; H,11.23.

EXAMPLE 49 N-(i cyclohexenyl)dimethylamine (62.5 g., 0.5 mole), methylacrylate (43 g., 0.5 mole), and acetonitrile ml.) which contained apinch of hydroquinone, were allowed to react keeping the temperature ofthe mixture below 30" C. by means of intermittent cooling. The solventwas removed by distillation under reduced pressure and the methyll-dimethylaminobicyclo[4.2.0]octane-8- carboxylate was then reduced withlithium aluminum hydride (13 g., 0.34 mole) as described in Example 48.The crude alcohol was heated for 2.5 hours on the steam bath with amixture of water (250 ml.) and concentrated bydrochloric acid (50 g.).The mixture was cooled, extracted twice with 50 ml. portions of ether,and the acidic aqueous phase was made basic with 10% sodium hydroxidesolution. The oil which separated was removed by extraction with ether.Distillation of the etheral extracts gave, after removal of ether and a2 g. forerun, 18.5 g. (21% based on starting methyl acrylate) ofl-dimethylaminobicyclo [4.2.0] octane-S-methanol, 13.1. 103-107 C. at 1mm., N 1.5043. Infrared and NMR spectra were consistent with theassigned structure.

AnalysIs.Calcd. for C H NO: C, 72.2; H, 11.5. Found: C, 72.05; H, 11.47.

EXAMPLE so Diethyl l-piperidinobicyc1o[3.2.0] heptane-6,7-dicarboxylate(161 g., 0.5 mole) was dissolved in ether (150 ml.) and the solutionadded dropwise with stirring to lithium aluminum hydride (25 g., 0.66mole) dissolved in ether (700 ml.). The addition, which required 5 hourswas done at such a rate so as to maintain gentle refluxing of the ether.The reaction mixture was allowed to stand overnight. Ethyl acetate (50ml.) was added to decompose excess hydride, followed by water (200 ml.).The solids were filtered off and washed with ether and the combinedetheral filtrate andl washings were evaporated on a steam bath. Theresidue crystallized to give 91 g. (76%) ofl-piperidinobicyclo[3.2.0]-heptane-6,7-dimethanol. A sample for meltingpoint analysis was purified by taking it up in 10% hydrochloric acid,extraction with ether to remove neutral impurities, remaking it basicwith dilute sodium hydroxide solution, and extraction with ether andevaporation on a steam bath. Recrystallization of the residue fromtoluene gave white crystals, Ml. 109-110 C. The infrared and NMR spectrawere consistent with the proposed structure.

Analysir.-Calcd. for C H NO C, 70.3; H, 10.5; N, 5.86; mol. wt. 23.9.Found: C, 70.62; H, 10.39; N, 5.53; mol. wt. 242.

EXAMPLE S1 Diethyl 1-dimethylaminobicyc1o[4.2.0]octane-7,8-dicarboxylate(90 g., ca. 0.3 mole) was reduced with lithium aluminum hydride (30 g.,0.79 mole) as described in Example 50. Distillation of the crude productgave 27.5 g. (43%, based on starting diethyl maleate) ofl-dimethylamln0bicyclo[4.2.0]octane-7,8-dimethanol, B.P. -165 C. at 1mm. The infrared spectrum was in agreement with the assigned structure.

A sample for analysis was purified as described in Ex- 15' ample S0. Thepurified material boiled at 156-157 C. at ca. 0.3 lama-Nb" 1.5140.

AnaIysis.-Calcd. for C H NOfi C, 67.7; H, 10.9. Foundz-C, 67.62; H,10.99.-

The following examples illustrate uses of the compounds of the'inveutionas fuel oil or gasoline additives and asanalgesics.

EXAMPLE 52 Utility as sludge and color stabilizers in petroleumhydrocarbons for several typicalcyclobutane'derivatives of the inventionwas determined by theCities Service Oil.

Company accelerated stability test as described in Anal. Chem. 24, i959(1952). Three hundred fifty ml. samples of No. 2 fuel oil containingthc'subject cyclobutane derivatives at concentrations equivalent to 50pounds of additive'per i000 barrels of oil, as well as control samplescontaining no additive, were heated at 100 C. in glass tubes while airwas blown through the oil for 16 hours. At the end of the heating periodthe samples were filtered through 7 cm. No. l Whatman filter paper, thetube and the paper rinsed with light naphtha, and thereafter the filterpaper air dried. The sludge retained on the filter paper was comparedvisually with a set of standard papers ranging from (no visible sludge)to (heavy black deposits). Also, the color of the aged oil wasdetermined with an A.S.T.M. Union Colorimeter. The results aresummarized in Table 1 below.

The derivatives prepared as described in Examples 43 to 47 were alsofound to have similar utility as sludge and color stabilizers in No. 2fuel oil when tested by the described Cities Service Test.

EXAMPLE 5 3 The cyclobutane derivatives of the invention in combinationwith phenolic materials are useful as antioxidants in cracked gasoline.Several sample: of gasoline containing 0.005% by weight ofp-n-butylaminophenol plus 0.001% by weight of one of the followingcyclobutane derivatives of the invention were subjected to the wellknownUOP oxygen bomb test:

(a) Diethyl 3,3-dimethyi-4-(lpiperidino)-l,2'cyclobutanedicarboxyiate;(b) 3,3-dimethyl-2-( i-piperidino) cyclobutanecarbonitrile;

an (e) Diethyl 3,3-dimethyl-4-dimethyiaminocyclobutane-1,2-dicarboxylate.

The induction period of gasoline by the U0? oxygen bomb test for each ofthe stabilizer'combinations was at least 835 minutes while that of thegasoline containing only 0.005% by weight of p-n-butylaminophenol was795 minutes. The induction period for gasoline containing only (a), (b)or (c) was no different from that of gasoline containing no additive atall.

EXAMPLE 54 This example shows analgesic effect on rate by the tail flicktest. This test is performed by uniformly blackening the tails of rats,administering an analgesic to the animal and subsequently focusing e.beam of light on the animal's tail at various intervals afteradministration of the analgesic. The time required for the animal toflick its tail after the beam of light is applied determines theanalgesic effect of the material being tested. The longer the intervalfor the tail flick, after the application of the concentrated beam oflight, the more effective is the analgesic. Predetermined dosages ofdiethyl 3,.3-dimethyl-4-dimethylaminocyclobutane 1,2 dicarboxyiate-HCl,D-propoxyphene-HCI and the very strong narcotic types of analgesics suchas morphine sulfate and codeine phosphate were given to rats. Eachmaterial was administered orally to' sets of fifteen animals except formorphine sulfate which was given subcutaneously to fifteen animals andcodeine phosphate which was given orally to twenty-five animals. Thefollowing quantities of each material were used: morphine sulfate, 1.5milligrams per kilogram weight of each animal; D-propoxyphene-HCl, 25milligrams per kilogram weight of each animal; codeine phosphate, 40milligrams per kilogram weight of each animal; and diethyl3,3-dimethyi-4-dimethylaminocyclobutane-1,2- dicarboxylate-HCI,milligrams per kilogram weight of each animal. The time in secondsduring which the animals could tolerate the concentrated beam of lightat various intervals after administration of the analgesics is given inTable 2 below. The values in the table are averages for the animals ineach set.

TABLE 2 Time in minutes after ndministrntlon oi mmlgoslc 20 40 iii) Timein seconds [or pain response of animals treated with- Morphine sulfate"i. 3 5. 8 0. 0 5. 3 D-propoxyphene liCl "4.3 5.7 5.0 4.9 Codeinephosphate "4. 3 6.8 5. 0 6. l Diothyl3,3-ditnethyH-dimethylatninocyclobutnnelJ-dlcurboxylute HCl "4. 3 5. 7h. 4 4. 9

immediately prior to administration 01 annlgesic.

Table 2 shows that an oral dose of 100 mg. of the cyclobutane compoundper kg. weight of the animal is equivalent in analgesic potency to oraldoses of either 25 mg./ kg. of D-propoxyphene-HCI or 4-0 mg./kg. ofcodeine phosphate and to a subcutaneous dose of 1.5 mg./kg. of morphinesulfate.

EXAMPLE 5 5 This example shows analgesic tests on rats by the tail flicktest as described in Example 54. Predetermined dosages of methyl3,3-dimethyl-4-dimethylaminocyclobutanel-carboxylate'HCl wereadministered orally to rats. Each dosage level contained five animalsand the results are given in Table 3, below, as the average time inseconds for the pain response of the animals in each dosage level.

This example shows anaiesic tests on rats by the tail flick test asdescribed in Example 54. Prcdctermined dosages of methyl2.2-dimethyi'3-(i-p lperidino)cyclobutnnol-curboxylate-HCl wereadmlnstercd orally to rats. Five animals were used with each dosagelevel. The results are given in Table 4 as the average time in secondsfor the pain response of the animals in each group.

TABLE 4 Time in minutes after administration of analgesic Time requiredin seconds for pain response:

150 mg. per kg *4. 4 5.0 4. 3 200 mg. per kg *4. 4 5.0 4. 7

'Immediately prior to administration of analgesic.

EXAMPLE 7 This example shows analgesic tests on rats by the tail flicktest as described in Example 54. The tests were performed with thefollowing nine compounds which were administered orally to rats.

Compound 1-1-(2,2-dimethyl-4-nitro-3-phenyl-cyclobutyl)piperidineCompound 2-3,3-dimethyl-2-(1-piperidino)cyclobutane-l-carbonitrileCompound 3-2,2-dimethyl-3-( l-piperidino)cyclobutylmethylamine Compound4-cyclobutanecarbonitrile 2-dimethylamino- 3,3-dimethyl Compound5--N,N,2,2-tetramethyl-4-methylsulfony1- cyclobutylamine Compound6N,N,4,4-tetramethyl-2-phenyl-2-cyclobutenamine Compound 7],4-bis(4-methoxycarbonyl-2,2-dimethylcyclobutyl)-piperazine Compound8-methyl 3,3-diethyl-2-(l-piperidino) cyclobutane-l-carboxylate Compound9secondary butyl 3,3dimethyl-2-dimethylaminocyclobutane-l-carboxylateThe results of the test are given in Table 5 below which shows theincrease in analagesic effect over control values for each compound atvarious time intervals and also at various dosages. The dosages areexpressed in milligrams of the active compound per kilogram weight ofthe animal. The time at which the animals were tested after theadministration of the analgesic is given in Table 5 below. Values arealso shown for aspirin and codeine which were run by the same method.The control value represents the time required for a tail flick by therats when tested by the method of Example 54 but when no analegesic isgiven to the animal. The control value is about 4.3 seconds.

Utility as sludge and color stabilizers in petroleum hydrocarbons forseveral typical cyclobutane derivatives of the invention was determinedby the Cities Service Oil Company accelerated stability test asdescribed in Anal. Chem. 24, 1959 (1951). Three hundred fifty ml.samples of No. 2 fuel oil containing the subject cyclobutane derivativesat concentrations equivalent to 50 pounds of additive per 1000 barrelsof oil, as well as control samples containing no additive, were heatedat 100 C. in glass tubes while air was blown through the oil for 16hours. At the end of the heating period the samples were filteredthrough 7 cm. N0. 1 Whatman filter paper, the tube and the paper rinsedwith light naphtha, and thereafter the filter paper air dried. Thissludge retained on the filter paper was compared visually with a set ofstandard papers ranging from 0 (no visible sludge) to 10 (heavy blackdeposits). Also, the color of the aged oil was determined with anA.S.T.M. Union Colorimeter. The results are summarized in Table 6 below.

The following examples illustrate the preparation of enamines that areuseful in the process of the invention.

EXAMPLE 59 The preparation of N,N-dibutyl isobutenyl amine wasaccomplished as follows. Isobutyraldehyde (180 g., 2.5 moles) was addedover a /s-hour period of dibutylamine. The reaction mixture was thenrefluxed under a Dean- Stark trap for 12 hours during which time 30 ml.of water was collected. Fractional distillation of the mixture gave,after removal of low boilers, 228 g. (63%) ofN,N-dibutylisobutenylamine, B.P. 70'.572 C. at 4.5-5.2 mm., N 1.4409.

EXAMPLE 60 In a manner similar to that described in Example 59,isobutyraldehyde and diisobutylamine gave N,N-diis0butylisobutenylamine,B.P. 64 C. at 5.8 mm., N 1.4375, in 57% yield.

EXAMPLE 61 In a manner similar to that described in Example 59,cyclohexanecarboxaldehyde and piperidine gave l-cyclohexylidenemethylpiperidine, B.P. 88 C. at 3 mm., N 1.5042, in yield.

EXAMPLE 62 In a manner similar to that described in Example 59,Z-ethylbutyraldehyde and piperidine gave N-(Z-ethyl-lbutenyl)piperidine,B.P. 103110 C. at 37-45 mm., N 1.4693, in 87% yield.

EXAMPLE 63 Over a 2-hour period isobutyraldehyde (400 g., 5 moles) wasadded to piperazine (172 g., 2 moles) at 35- 40 C. The mixture wasstirred and refluxed under a Dean- Stark trap for 7 hours, during whichtime 74 ml. of water was collected. Distillation of the reaction mixturegave, after removal of low boilers, 221 g. (57%) of 1,4-disobutenylpiperazine, B.P. 70-75 C. at 2 mm., MP. 35-- 37 C.

EXAMPLE 64 A chilled mixture of isobutyraldehyde (288 g., 4 moles), 500ml. of xylene and 150 g. of anhydrous potassium carbonate was charged toan autoclave. Then dimethylamine (200 g., 4.4 moles) was added and theautoclave was closed and heated at C. for 4 hours. The autoclave wasallowed to cool, was vented cautiously and discharged. The mixture wasfiltered by gravity and the filtrate was distilled to give, afterremoval of unreacted starting materials, 198 g. (50%) ofN,N-dimethylisobutylenamine, B.P. 87-89 C., N 1.4219.

The novel esters of my invention in which Y or Z or both arealkoxycarbonyl groups are useful as chemical intermediates in thepreparation of carboxamides Which are useful for a number of purposes,for example, as analgesics, as stabilizers for fuel oil, etc., asdisclosed in U.S. Patent 3,133,924. The amides can be prepared from myesters by reacting a methanolic solution of a compound of my inventionin which either Y or Z or both are alkoxycarbonyl groups with ammonia ora primary or secondary amine, preferably in the presence of sodiummethoxide.

The following example illustrates such a preparation.

EXAMPLE 65 An 18.5 g. portion of methyl3,3-dimethyl-2-dimethylaminocyclobutane carboxylate was dissolved in 100ml. of methanol and 8 g. of anhydrous ammonia was bubbled therethrough.The solution was allowed to stand at room temperature for 8 days. Thesolution was then evaporated on a steam bath and the resulting residuetaken up in n-hexane and filtered. The resulting filtered precipitatewas washed with diethyl ether to give 0.8 g. of 3,3-dimethyl 2dimethylaminocyclobutane carboxamide, M.P. 142 C.

Although the invention has been described in considerable detail withparticular reference to certain preferred embodiments thereof,variations and modifications can be effected within the spirit and scopeof the invention as described hereinbefore and as defined in theappended claims.

I claim:

1. A tertiaryaminocyclobutane having the formula:

wherein X is a tertiaryamino group having a formula selected from thegroup consisting of Y is nitrile; Z is selected from the groupconsisting of hydrogen, phenyl, and nitrile; wherein each of R and Rwhen taken singly, is lower alkyl R and R when taken collectively withthe carbon atom to which they are attached, represent a saturatedcarbocyclic group selected from the group consisting of:

(a) cyclobutylidene, (b) cyclopentylidene, (d) cycloheptylidene, and (e)cyclooctylidene; wherein each of R and R when taken singly, is loweralkyl and R and R when taken collectively with the nitrogen atom towhich they are attached, represent a heterocyclic group selected fromthe group consisting of:

(a) pyrrolidino, (b) piperidino, and (c) morpholino; wherein each of thesubstituents R is an ethylene group. 2. A tertiaryaminocyclobutanehaving the formula:

wherein X is a tertiaryamino group having a formula selected from thegroup consisting of:

Y is nitrile; Z is selected from the group consisting of hydrogen,phenyl, and nitrile; wherein R is selected from the group consisting of:

(a) lower alkyl, (b) phenyl, and (c) tertiaryaminomethyl of the formula-CH X; wherein each of the R and R when taken singly, is a lower alkyland R and R when taken collectively with the nitrogen atom to which theyare attached, represent a heterocyclic group selected from the groupconsisting of:

(a) pyrrolidine, (b) piperidino, and (c) morpholino; and wherein each ofthe substituents R is an ethylene group. 3. A tertiaryaminocyclobutanehaving the formula:

wherein X is a tertiaryamino group having a formula selected from thegroup consisting of:

Y is nitrile; Z is selected from the group consisting of hydrogen,phenyl, and nitrile; wherein each of R and R when taken singly, is loweralkyl and R and R when taken collectively with the carbon atoms to whichthey are attached, represent a group selected from the group consistingof:

(a) 1,2-cyclopentylene, (b) 1,2-cyclohexylene, (c) 1,2-cycloheptylene,(d) 1,2-cyclooctylene, (e) tetrahydrofuran-3,4-ylene, (f)tetrahydrofuran-2,3-ylene, (g) N-methylpiperidin-2,3-ylene, and (h)N-methylpiperidin-3,4-ylene; wherein each of R and R when taken singly,is lower alkyl and R and R when taken collectively with the nitrogenatom to which they are attached, represent a heterocyclic group selectedfrom the group consisting of:

(a) pyrrolidino, (b) piperidino, and (c) morpholino; and wherein each ofthe substituents R is an ethylene group. 4. The process for preparing atertiaryaminocyclobutane which comprises contacting an enamine of theformula:

with a substituted olefin of the formula:

YCH=OHZ at a temperature of about C. to about 200 C. and obtaining atertiaryaminocyclobutane of the formula:

R2 X-(lH-t'J-R Y-CHCH-Z wherein X, of the enamine, is a tertiaryaminogroup having a formula selected from the group consisting of:

and

R tain-N 1% and X, of the tertiaryaminocyclobutane, is a tertiary aminogroup having a formula selected from the group consisting of:

Y is nitrile; Z is hydrogen, phenyl, or nitrile; wherein each of R and Rwhen taken singly, is alkyl of 1 to 18 carbons and R and R when takencollectively with the carbon atom to which they are attached, representa saturated carbocyclic group having 4 to 8 ring carbons selected fromthe group consisting of:

(a) cyclobutylidene, (b) cyclopentylidene, (c) cyclohexylidene, (d)cycloheptylidene, and (e) cyclooctylidene; wherein each of R and R whentaken singly, is alkyl of 1 to 18 carbons and R and R when takencollectively with the nitrogen atom to which they are attached,represent a saturated heterocyclic group having 5 to 6 ring atomsselected from the group consisting of pyrrolidino, piperidino, andmorpholino; and each of the substituents R is an alkylene group of 2carbon atoms. 5. The process for preparing a tertiaryaminocyclobu- 5tane which comprises contacting an enamine of the formula:

XCH=CHR3 with a substituted olefine of the formula:

and X, of the tertiaryaminocyclobutane, is a tertiaryamino group havinga formula selected from the group consisting of:

Y is nitrile; Z is hydrogen, phenyl, or nitrile; wherein R is selectedfrom the group consisting of:

(a) alkyl of 1 to 18 carbons, (b) phenyl, and (c) tertiaryaminomethyl ofthe formula -CH X; wherein X is defined above with respect to thetertiaryaminocyclobutane; wherein each of R and R when taken singly, isalkyl of 1 to 18 carbons and R and R when taken collectively with thenitrogen atom to which they are attached, represent a saturatedheterocyclic group having 5 to 6 ring atoms selected from the groupconsisting of pyrrolidino, piperidino, and morpholino; and each of thesubstituents R is an alkylene group of 2 carbon atoms. 6. The processfor preparing a tertiaryaminocyclobutane which comprises contacting anenamine of the formula:

R1 X-(I3=CHR3 with a substituted olefin of the formula:

Y-CH=CHZ at a temperature of about 0 C. to about C. and

obtaining a tertiaryaminocyclobutane of the formula:

l X-C('3H-R3 Y-CiI-OH-Z wherein X, of the enamine, is a tertiaryaminogroup having a formula selected from the group consisting and X, of thetertiaryaminocyclobutane, is a tertiaryamino group having a formulaselected from the group consisting of:

Y is nitrile; Z is hydrogen, phenyl, or nitrile; wherein each of R and Rwhen taken singly, is alkyl of 1 to 18 carbons and R and R when takencollectively with the carbon atoms to which they are attached, representa group having 5 to 8 ring atoms selected from the group consisting of:

(a) 1,2-cycl0pentylene, (b) 1,2-cycl0hexylene, (c) 1,2-cycloheptylene,(d) 1,2-cyclooctylene, (e) tetrahydrofuran-3,4-ylene, (f)tetrahydrofuran-Z,3-ylene, (g) N-methylpiperidin-2,3-ylene, and

(h) N-rnethylpiperidin-3,4-ylene; References Cited wherein each of R andR when taken singly, is alkyl ATE PA of 1 to 18 carbons and R and R whentaken 001- UNITED ST S TENTS lectively with the nitrogen atom to whichthey are 3,051,622 8/1962 q at 31 167-65 attached, represent a saturatedheterocyclic group 5 3,133,924 5/1964 Wilson et 260268 having 5 to 6ring atoms selected from the group consisting of pyrrolidino,piperidino, and morpho- HENRY JILESPnmary Exammer lino; R. T. BOND,Assistant Examiner and each of the substituents R is an alkylene groupof 2 carbon atoms. 10 U8. C1. X.R.

7. A COIllpOUDd according t0 claim 2 in which the corn- 44 3 74. 252 47475. 2 250 267 274 pound is3,3-dimethyl-2-(piperidino)cyclobutanecarboni- 325 trile.

8. A compound according to claim 2 in which the compound is3,3-dimethyl-2-dimethylaminocyclobutanecar- 15 bonitrile.

